Prefrontal allopregnanolone mediates the adverse effects of acute stress in a mouse model of tic pathophysiology

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2023-08, Vol.48 (9), p.1288-1299
• Main Authors: Cadeddu, Roberto, Van Zandt, Meghan, Santovito, Luca Spiro, Odeh, Karen, Anderson, Collin J, Flanagan, Deirdre, Nordkild, Peter, Pinna, Graziano, Pittenger, Christopher, Bortolato, Marco
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Disease Models, Animal; Female; Gilles de la Tourette syndrome; Grooming; Interneurons; Male; Mice; Neostriatum; Pathophysiology; Prefrontal cortex; Pregnanolone; Pregnanolone - pharmacology; Side effects; Stereotyped Behavior; Tics; Tourette Syndrome
• ISSN: 0893-133X; 1740-634X; 1740-634X
• DOI: 10.1038/s41386-023-01603-6

Ample evidence suggests that acute stress can worsen symptom severity in Tourette syndrome (TS); however, the neurobiological underpinnings of this phenomenon remain poorly understood. We previously showed that acute stress exacerbates tic-like and other TS-associated responses via the neurosteroid allopregnanolone (AP) in an animal model of repetitive behavioral pathology. To verify the relevance of this mechanism to tic pathophysiology, here we tested the effects of AP in a mouse model recapitulating the partial depletion of dorsolateral cholinergic interneurons (CINs) seen in post-mortem studies of TS. Mice underwent targeted depletion of striatal CINs during adolescence and were tested in young adulthood. Compared with controls, partially CIN-depleted male mice exhibited several TS-relevant abnormalities, including deficient prepulse inhibition (PPI) and increased grooming stereotypies after a 30-min session of spatial confinement - a mild acute stressor that increases AP levels in the prefrontal cortex (PFC). These effects were not seen in females. Systemic and intra-PFC AP administration dose-dependently worsened grooming stereotypies and PPI deficits in partially CIN-depleted males. Conversely, both AP synthesis inhibition and pharmacological antagonism reduced the effects of stress. These results further suggest that AP in the PFC mediates the adverse effects of stress on the severity of tics and other TS-related manifestations. Future studies will be necessary to confirm these mechanisms in patients and define the circuitry responsible for the effects of AP on tics.